Project Summary Environment: The University of California (UC) is a leading academic research institution where senior scientists have a long-standing tradition of training the next generation of scientists at UC, where seven percent of the nation?s Ph.D.?s are awarded each year and more than six thousand post-doctoral fellows choose to conduct their research. The UC campus in San Diego (UCSD) is key component, excelling at collaborative and innovative biological science. The environment here is rich in scientific discussion, training and exposition, with the Salk and Sanford-Burnham institutes within walking distance. Dr. Grainger has access to a wide variety of training sessions, classes and seminars for personal development and expansion of her scientific and leadership skills. There are a wealth of career development seminars available to be attended on a weekly basis, in addition to the innumerable scientific seminars. Research efforts are able to run smoothly here, due to the abundance of core facilities and expertise available in any area of science. Candidate: Dr. Grainger is a postdoctoral fellow in David Traver?s lab at UCSD whose ultimate career goal is to lead a research lab focused on stem cells at an R1 University. She was recruited to join Dr. Traver?s lab because of her strong background in developmental biology, Wnt signaling and animal models. Over the past 3.5 years, she has been working in collaboration with Dr. Karl Willert?s lab at UCSD, which has led to two publications: One is now published at Cell Reports; the second is currently in press at Zebrafish. Dr. Grainger is a leader in the lab, having established this project and being the driving force of the collaborative efforts of the Traver-Willert group. She is also a leader outside of the lab, where she organizes a postdoc seminar series focused on stem cells, enriching the community around her. She is well poised to execute the proposed work, achieve her career development and training goals and to contribute high impact research to the scientific community. Research: All mature blood cells are derived from hematopoietic stem cells (HSCs). Generating HSCs in vitro from pluripotent precursors such induced pluripotent stem cells would allow us to treat diseases such as leukemias and lymphomas with in vitro derived HSCs, circumventing the need for bone marrow donation. This would also establish an important cellular tool for understanding the underlying mechanisms of hematopoietic diseases. The overarching goal of this proposal is to gain a better understanding of one of the developmental cues that instruct HSC fate from mesoderm, the Wnt signaling cascade. This study will be conducted in zebrafish, which are an ideal system for direct visualization of blood stem cells and have conserved genetics. I hypothesize that an early Wnt/Fzd cue regulates later HSC amplification, which has an impact on adult HSC homeostasis. I propose to test this hypothesis by 1. Characterizing the Wnt/Fzds required, 2. Determining what happens downstream of this signal at the transcriptome level and 3. Discovering how this affects HSC homeostasis.